Farmakoterapi

Systemic Lupus
Erythematosus
 01 Menjelaskan manifestasi klinis
dan komplikasi SLE

Kompetensi Menjelaskan patofisiologi SLE

02 dan mekanisme terjadinya
komplikasi

03 Memberikan rekomendasi rencana

terapi dan menyampaikan ke
Spesialis Rheumatologi

04 Memberikan rekomendasi
pemantauan terkait SLE dan
terapi

2
 Chronic inflammatory disease —>
Systemic various manifestation —> follows
a relapsing and remitting course
Lupus Characterized by —> autoantibody
Erythematosus response to nucleus & cytoplasmic
antigens
 01 Menjelaskan manifestasi klinis
dan komplikasi SLE

Kompetensi Menjelaskan patofisiologi SLE

02 dan mekanisme terjadinya
komplikasi

03 Memberikan rekomendasi rencana

terapi dan menyampaikan ke
Spesialis Rheumatologi

04 Memberikan rekomendasi
pemantauan terkait SLE dan
terapi

4
Fast Fact
01 Lupus affects 10 times as many women as
men

02 Treatment depends on the symptoms and how

serious they are

Because it is a complex disease, lupus

03 requires treatment by or consultation with
a rheumatologist, a doctor who is an
expert in treating diseases like lupus

04 People can live well with lupus if they

actively work toward good health.
6 Pathogenesis and pathophysiology activation of antigen-presenting cells (figure 3). Once
Immune responses against endogenous nuclear antigens initiated, immune reactants such as immune complexes
Pathogenesis
are characteristic of SLE. Autoantigens released by amplify and sustain the inflammatory response.

Figure 3 In systemic lupus erythematosus all pathways lead to endogenous nucleic acids-mediated production of interferon α (IFNα).
Increased production of autoantigens during apoptosis (UV-related and/or spontaneous), decreased disposal, deregulated handling and
presentation are all important for the initiation of the autoimmune response. Nucleosomes containing endogenous danger ligands that
can bind to pathogen-associated molecular pattern receptors are incorporated in apoptotic blebs that promote the activation of DCs and
B cells and the production of IFN and autoaantibodies, respectively. Cell surface receptors such as the BCR and FcRIIa facilitate the
endocytosis of nucleic acid containing material or immune complexes and the binding to endosomal receptors of the innate immunity
 HLA-A1, B8, and DR3 are more common in

Etiology
01 persons with SLE than in the general
population

The presence of the null complement

02 alleles and congenital deficiencies of

complement (especially C4, C2, and other
early components)

03 Viruses may stimulate specific cells in

the immune network, e.g: Epstein-Barr
virus (EBV)

Chronic infections may induce anti-DNA

04 antibodies or even lupus-like symptoms,

and acute lupus flares often follow
bacterial infections

05 vitamin D deficiency was also linked to B-

cell hyperactivity and interferon-alpha
activity
Epidemiology 01 52 kasus per 100.000 penduduk (USA) —>
perempuan:laki-laki (9-14:1)

1.4% kasus SLE dari total kunjungan pasien

02 di poliklinik Reumatologi Penyakit Dalam
(RSCM tahun 2002)

03 10.5% dari total pasien yang berobat ke

poliklinik reumatologi (RS Hasan Sadikin
tahun 2010)

04 70% of SLE: females between ages 15-45

•10% present age >60

05 Highest occurrence is in Afro-Caribbean

females 1:250
Prognosis & SLE is milder & survival rate higher among

Mortality 01 persons with isolated skin &

musculoskeletal involvement than in those
with renal & CNS disease

02 •Prior to 1955 à 5-year survival rate < 50%

•Now à 10-year survival rate > 90% (USA), the
15-year survival rate is approximately 80%

03 •90% survive 5 years, 80% 10 years

•Renal disease causes worse prognosis

04 African Americans have more aggressive and

treatment resistant disease

Two different causes of death:

•Early: disease activity and infections

05 •Late: cardiovascular disease, disease

activity, end stage renal disease, and
thromboembolic
 Manifestasi
Klinis
Umum:
•artritis 48,1%
•ruam malar 31,1%
•nefropati 27,9%
•fotosensitiviti 22,9%
•keterlibatan neurologik 19,4%
•demam 16,6%

jarang:
•miositis 4,3%
•ruam diskoid 7,8%
•anemia hemolitik 4,8%
•lesi subkutaneus akut 6,7%
 The Systemic Lupus International
Collaborating Clinics (SLICC)
group revised and validated the
SLE classification criteria in
Approach 2012 a patient is classified as
having SLE if the patient has
Considerations biopsy-proven lupus nephritis
of Criteria with ANA or anti-dsDNA, or the
patient satisfies four of the
criteria, including at least one
clinical and one immunologic
criterion
 Criteria Definition
Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic
scarring occurs in older lesions
Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician
observation

Kriteria
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician
Arthritis Non-erosive arthritis involving two or more peripheral joints, characterised by tenderness,
swelling or effusion
Serositis a. Pleuritis: convincing history of pleuritic pain or rub heard by a physician or evidence of
pleural effusion or
b. Pericarditis: documented by ECG or rub or evidence of pericardial effusion
Renal disorder a. Persistent proteinuria >0.5 g per day or >3+ if quantitation is not performed or
b. Cellular casts: may be red cell, haemoglobin, granular tubular, or mixed
Neurological disorder a. Seizures: in the absence of offending drugs or known metabolic derangements (eg, uraemia,
acidosis, or electrolyte imbalance) or
b. Psychosis: in the absence of offending drugs or known metabolic derangements
(eg, uraemia, acidosis, or electrolyte imbalance)
Haematologic disorder a. Haemolytic anaemia with reticulocytosis, or
b. Leucopenia: <4000/mm3, or
c. Lymphopenia: <1500/mm3, or
d. Thrombocytopenia: <100 000/mm3 in the absence of offending drugs
Immunologic disorder a. Anti-DNA: antibody to native DNA in abnormal titre, or
b. Anti-Sm: presence of antibody to Sm nuclear antigen, or
c. Positive finding of antiphospholipid antibodies based on: (1) an abnormal serum
concentration of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus
anticoagulant using a standard method, or (3) a false positive serologic test for syphilis
known to be positive for at least 6 months and confirmed by Treponema pallidum
immobilisation or fluorescent treponemal antibody absorption test
Antinuclear antibody An abnormal titre of antinuclear antibody by immunofluorescence or an equivalent assay at
any point in time and in the absence of drugs known to be associated with ‘drug-induced
lupus’ syndrome
 ANA test • Sensitivity 95%
Screening laboratory
studies to diagnose
Anti-dsDNA • High specificity; sensitivity only 70%
possible SLE
Anti-Sm • 30-40% sensitivity

Anti-SSA (Ro) or Anti- • Present in 15% of patients with SLE and other connective-tissue 1.Hemoglobin, lekosit, hitung
SSB (La) diseases jenis sel, laju endap darah
(LED)*
Anti-ribosomal P • Correlate with risk for CNS disease 2.Urin rutin dan mikroskopik,
protein kwantitatif 24 jam, dan
Anti-RNP • Included with anti-Sm, SSA, and SSB in the ENA profile bila diperlukan kreatinin urin.
3.Kimia darah (ureum, kreatinin,
• IgG/IgM variants measured with enzyme-linked immunoassay (ELISA) fungsi hati, proil lipid)*
Anticardiolipin are among the antiphospholipid antibodies used to screen for 4.PT, aPTT pada sindroma
antifosfolipid
antiphospholipid antibody syndrome and pertinent in SLE diagnosis 5.Serologi ANA § , anti-dsDNA † ,
komplemen † (C3,C4))
Lupus anticoagulant • Multiple tests (eg, direct Russell viper venom test) 6.Foto polos thorax
Direct Coombs test • Coombs test–positive anemia to denote antibodies on RBCs

• Drug-induced lupus ANA antibodies are often of this type (eg, with
Anti-histone procainamide or hydralazine; perinuclear antineutrophil cytoplasmic
antibody [p-ANCA]–positive in minocycline-induced drug-induced lupus)
 Renal Class Classification Features

Biopsy Class I Minimal mesangial

Normal light microscopy
findings; abnormal
electron microscopy
findings

Hypercellular on light
Class II Mesangial proliferative
microscopy

< 50% of glomeruli

Class III Focal proliferative
involved

>50% of glomeruli
involved; classified
Class IV Diffuse proliferative
segmental or global;
treated aggressively

Predominantly nephrotic
Class V Membranous
disease

Chronic lesions and

Class VI Advanced sclerosing
sclerosis
 Ringan:
•Secara klinis tenang
•Tidak terdapat tanda atau gejala yang mengancam nyawa
Kategori 01 •Fungsi organ normal atau stabil, yaitu: ginjal, paru,
jantung, gastrointestinal, susunan saraf pusat, sendi,
hematologi dan kulit.
SLE •contoh: SLE dengan manifestasi arthritis dan kulit.

Sedang:

02 •Nefritis ringan sampai sedang ( Lupus nefritis

kelas I dan II)
•Trombositopenia (trombosit 20-50x10 3 /mm3)
•Serositis mayor

Berat atau Mengancam jiwa:

• Jantung: endokarditis Libman-Sacks, vaskulitis arteri koronaria,
miokarditis, tamponade jantung, hipertensi maligna.

03 • Paru-paru: hipertensi pulmonal, perdarahan paru, pneumonitis, emboli

paru, infark paru, ibrosis interstisial, shrinking lung.
• Gastrointestinal: pankreatitis, vaskulitis mesenterika.
• Ginjal: nefritis proliferatif dan atau membranous.
• Kulit: vaskulitis berat, ruam difus disertai ulkus atau melepuh
(blister).
• Neurologi: kejang, acute confusional state, koma, stroke, mielopati
transversa, mononeuritis, polineuritis, neuritis optik, psikosis,
sindroma demielinasi.
• Hematologi: anemia hemolitik, neutropenia (leukosit <1.000/mm 3 ),
trombositopenia < 20.000/mm 3 , purpura trombotik trombositopenia,
trombosis vena atau arteri.
Goals of 01 Long term survival

Therapy 02 Lowest possible disease activity

03 Prevent organ damage

04 Minimize drug toxicity

05 Improve quality of life

06 Educate patients about their role in

disease management

07 Individualized treatment of SLE based upon disease

activity, severity, and co-morbidities

08 Monitoring of disease and Multiorgan system

involvement may require multidisciplinary care
 Antimalarials and/or glucocorticoids à SLE without major
organ manifestations à if nonresponsive or who cannot

01 reduce steroids doses below those acceptable for long-term

use à immunosuppressive agents (eg. azathioprine,
mycophenolate mofetil, & methotrexate)

SLE treatments
based on The 02 In patients at low risk for complications from NSAIDs
à may be used judiciously for limited periods

European League Prednisolone, hydroxychloroquine, and low-dose

Against
Rheumatism
03 aspirin may be used in pregnancies of women with
lupus, but azathioprine, mycophenolate mofetil,
cyclophosphamide, and methotrexate must be avoided

(EULAR) In patients with SLE and antiphospholipid antibodies, low-

recommendation 04 dose aspirin may be useful for primary prevention of

thrombosis & pregnancy loss or anticoagulant for secondary
prevention of thrombosis in nonpregnant patients with SLE

Glucocorticoids in combination with immunosuppressive

05 agents are effective against progression to end-stage

renal disease in patients with proliferative lupus
nephritis
 01 who do not respond to corticosteroids alone,

02 who have unacceptable toxicity to corticosteroids

Immunosuppressive
drugs indication 03 who have worsening renal function

04 who have severe proliferative lesions, or

05 who have evidence of sclerosis on renal biopsy specimens

 •MOA: propably impair complement-dependent
antigen-antibody reactions; inhibits
locomotion of neutrophils and chemotaxis
of eosinophils
•400 mg (310 mg base) PO once or twice
daily; maintenance: 200-400 mg (155-310 mg
base) PO daily
Antimalarias •Contraindications: Hypersensitivity to 4-
aminoquinoline derivatives, porphyria,
psoriasis, long-term therapy in children
•Discontinue in 6 months if improvement is
inadequate
•Retinal damage and loss of visual acuity
may occur with long-term use
 • 500 mg IV every 2 weeks (or 500-1000 mg/m² IV monthly) for 6
doses plus corticosteroids, then maintenance with mycophenolate
mofetil or azathioprine (lupus nephritis)
Cyclophosphamide • Hepatic impariment à 75% of normal dose if transaminase >3 times
upper limit of normal or bilirubin is 3.1-5 mg/dL
• Renal impairment à CrCl <10 mL/min à 75% of normal dose
• Contraindication à Severe myelosuppression, hypersensitivity

• 2 mg/kg/day PO with or without low dose corticosteroids (lupus

nephritis)
Immunosuppressive Azathioprine
• Contraindication à Hypersensitivity, pregnancy, lactation, previously
agents treated with alkylating agents

• MOA à Inhibits T- & B-cell proliferation, & AB production

• Class III/IV lupus nephritis à 2-3 g PO qDay for 6 months
• Administer with initial IV corticosteroid pulse (3 days) & then
prednisone 0.5-1 mg/kg/day PO à after a few weeks, taper
Mycophenolate
prednisone to lowest effect dose
• If improved after 6 months, decrease dose to 1-2 g/day; if not
improved, switch to cyclophosphamide
• Take on empty stomach 1 hr before or 2 hr after meals
 The monoclonal antibody belimumab (B-lymphocyte stimulator–
specific inhibitor) has been found to reduce disease

01 activity & possibly decrease the number of severe flares &

steroid use in patients with SLE, when used in combination
with standard therapy

In March, 2011, the US FDA approved the use of

02 belimumab in combination with standard therapies to
treat active autoantibody-positive SLE

Biological 03 Patients of African American or African descent did

not show significant responses to belimumab
Treatment B-cell depletion with rituximab (Rituxan) has been used

04 successfully for rheumatoid arthritis à Recent studies

have shown mixed results for the treatment of SLE

05 Further studies are needed to define the best role for

this treatment in active SLE
Patients with severe active lupus nephritis or CNS lupus,

06 or those previously treated with other biologics or

cyclophosphamide, have been excluded from participation
in early trials
Bological approach
 Algoritma penatalaksanaan SLE dapat dilihat dibawah ini

penatalaksanaan SLE
Algoritma

Ket:
KS adalah
kortikosteroid setara
prednison, MP
metilprednisolon, AZA
azatioprin, OAINS
obat anti in lamasi
steroid, CYC
siklofosfamid, NPSLE
neuropsikiatri SLE.
 TABLE 1

Treatment recommendations for systemic lupus erythematosus (SLE) with no, mild, and/or moderate organ manifestations
(e.g., skin, joints, serositis)
German Society of Indication Medication Level of Strength of statement Dosage
evidence
First line and basic treatment Hydroxychloroquine 2 (21) A (21) ≤ 6.0–6.5 mg/kg ideal body weight/day
or
Chloroquine ≤ 3.5–4.0 mg/kg ideal body weight/day
Calculation of ideal body weight:
– Men: [Height minus 100] minus 10%
– Women: [Height minus 100] minus 15%
If indicated, initial non- – D
steroidal anti-inflamma-
Rheumatology

tory drugs

and/or
glucocorticoids 2 A
If no response or no reduc- Azathioprine 4 (21) B (21) 2–3 mg/kg body weight/day
tion of glucocorticoids or
≤ 7.5 mg possible in the long methotrexate 2 (21) A (21) 15–20 mg/week (preferably s.c.)
term or
mycophenolate mofetil* 6 (21) D (21) 2 g/day
Adjunct treatment in Belimumab – 10 mg/kg body weight i.v. infusion (1 h) initially, then after
autoantibody-positive SLE 14 days and subsequently every 4 weeks
with high disease activity
despite standard treatment
(e27)
Remarks:
– According to expert opinion, not only low-dose prednisone but also hydroxychloroquine and azathioprine (particularly in lupus nephritis [10]) can be
administered in pregnancy (e20).
– In case of comedication with mycophenolate mofetil and proton pump inhibitors, the bioavailability of mycophenolate mofetil is reduced; a switch to
mycophenolic acid is advisable (e32).
– Proton pump inhibitors may lower the efficacy of hydroxychloroquine/chloroquine (e33).
– Treatment and monitoring instructions of the DGRh (in German) for the above-mentioned medications for use by patients and physicians can be found at
www.dgrh.de/therapieueberwachen.html
 TABLE 2

Treatment recommendations on the example of proliferative lupus nephritis class III–IV in systemic lupus erythematosus with active organ
involvement (ISN/RPS, International Society of Nephrology/Renal Pathology Society 2003 Classification of Lupus Nephritis) (11)

German Society of Indication Medication Level of Strength of statement Dosage

evidence
Continuation of treatment Hydroxychloroquine 3 (10) C (10) ≤ 6.0–6.5 mg/kg ideal body weight/day
with antimalarials
Induction therapy Combination of
glucocorticoids Begin with methylprednisolone 500–750 mg i.v. on
3 consecutive days (level of evidence 3, strength of
statement C); then glucocorticoids per os 0.5 mg/kg body
weight/day for 4 weeks with subsequent tapering
(strength of statement C)
with:
mycophenolate mofetil 1 (10) A (10) 3 g/day or mycophenolic acid 2.16 g/day for 6 months,
respectively (especially with marked proteinuria)
or
Rheumatology

cyclophosphamide 1 (10) B (10) Total dose of 3 g (6 × 500 mg every 2 weeks) over

(low-dose) i.v. 3 months

or
azathioprine 2 (10) B (10) 2 mg/kg body weight/day, in selected patients without
adverse prognostic factors or if mycophenolate mofetil or
cyclophosphamide are contraindicated, not tolerated, or
unavailable
Maintenance treatment after Combination of low- 5.0–7.5 mg/day prednisone
response to induction dose glucocorticoids
therapy with:
mycophenolate mofetil 1 (10) A (10) 2 g/day or mycophenolic acid 1.44 g/day

or
azathioprine* 1 (10) A (10) 2 mg/kg body weight/day
mycophenolate mofetil or azathioprine for 3 years,
respectively (level of evidence 3, strength of statement
C); then begin with slow tapering of glucocorticoids
Refractory to therapy, or Calcineurin inhibitors –
contraindication (cyclosporine A, tacroli-
mus)
–
Rituximab (anti-CD20)
Remarks:
– According to expert opinion, not only low-dose prednisone but also hydroxychloroquine and azathioprine (particularly in lupus nephritis [10]) can be
administered in pregnancy (e20).
– In case of comedication with mycophenolate mofetil and proton pump inhibitors, the bioavailability of mycophenolate mofetil is reduced; a switch to
mycophenolic acid is advisable (e32).
– Proton pump inhibitors may lower the efficacy of hydroxychloroquine/chloroquine (e33).
– Treatment and monitoring instructions of the DGRh (in German) for the above-mentioned medications for use by patients and physicians can be found at
www.dgrh.de/therapieueberwachen.html
Treatment approach
for LN
 01 Penjelasan tentang apa itu lupus dan penyebabnya.

02 Tipe dari penyakit SLE dan perangai dari masing-

masing pe tersebut.

Masalah yang terkait dengan fisik: kegunaan lahan terutama

Edukasi dan 03 yang terkait dengan pemakaian steroid seper osteoporosis,

israhat, pemakaian alat bantu maupun diet, mengatasi
infeksi secepatnya maupun pemakaian kontrasepsi.
Konseling Pengenalan masalah aspek psikologis: bagaimana pemahaman

04 diri pasien SLE, mengatasi rasa lelah, stres emosional,

trauma psikis, masalah terkait dengan keluarga atau tempat
kerja dan pekerjaan itu sendiri, mengatasi rasa nyeri.

05 Pemakaian obat mencakup jenis, dosis, lama pemberian dan

sebagainya.

06 Dimana pasien dapat memperoleh informasi tentang SLE

“you may see me
STRUGGLE
but
You will never
see me FAAL.”

- Surname